4-cyanopyrazole-3-carboxamide derivatives, preparation, and application thereof

ABSTRACT

The invention relates to 4-cyanopyrazole-3-carboxamide derivatives of formula (I): 
                         
in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  are as described herein. Also disclosed and claimed are the method of preparation and therapeutic application of compound of formula (I).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International application No.PCT/FR2004/001,580, filed Jun. 24, 2004, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofFrench Patent Application No. 03/07,698, filed Jun. 25, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 4-cyano-pyrazole-3-carboxamidederivatives, their preparation and their therapeutic application.

2. Description of the Art

A 4-cyanopyrazole-3-carboxamide derivative is known:N-phenyl-1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamidewhich is described in Biochem. Pharmacol., 2000, 60(9), 1315-1323. It ispresented as having antagonist properties for the CB₁ cannabinoidreceptors and more precisely inverse agonist properties for saidreceptors.

SUMMARY OF THE INVENTION

The subject of the present invention is a compound corresponding toformula (I):

in which:

-   -   R₁ represents hydrogen or a (C₁-C₄)alkyl;    -   R₂ represents:        -   a (C₃-C₇)alkyl group;        -   a nonaromatic C₃-C₁₀ carboxyl radical which is unsubstituted            or substituted once or several times with a (C₁-C₄)alkyl            and/or hydroxyl group;        -   a phenyl which is substituted once or several times with a            halogen atom and/or with a (C₁-C₄)alkyl and/or            trifluoromethyl and/or (C₁-C₄)alkoxy group;        -   an NR₉R₁₀ group;        -   a CH[(C₁-C₄)alkyl]benzhydryl group in which one or both of            the phenyl groups are unsubstituted or substituted once or            several times with a halogen atom and/or with a (C₁-C₄)alkyl            and/or (C₁-C₄)alkoxy group;    -   or R₁ and R₂ together with the nitrogen atom to which they are        attached constitute a piperidin-1-yl radical which is        disubstituted at the 4-position with a phenyl or benzyl group        and with a (C₁-C₄)alkyl group or a (C₁-C₃)alkanoyl;    -   R₃, R₄, R₅, R₆, R₇, R₈ represent, each independently of the        other, a hydrogen or halogen atom, a (C₁-C₆)alkyl, (C₁-C₆)alkoxy        or trifluoromethyl group; provided that at least one of the        substituents R₃, R₄, R₅, R₆, R₇, R₈ is different from hydrogen;    -   R₉ represents a hydrogen atom;    -   R₁₀ represents a (C₃-C₆)alkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached constitute a saturated or unsaturated heterocyclic        radical of 5 to 10 atoms, possibly containing a second        heteroatom chosen from O or N, said radical being unsubstituted        or substituted once or several times with a (C₁-C₄)alkyl and/or        hydroxyl and/or (C₁-C₄)alkoxy and/or methoxy(C₁-C₂)alkylene        and/or (C₁-C₄)alkanoyl group, or substituted with a        spirocyclobutane, a spirocyclopentane or a spirocyclohexane; and        their salts, their solvates and their hydrates.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) may contain one or more asymmetric carbonatoms. They can therefore exist in the form of enantiomers ordiastereoisomers. These enantiomers, diastereoisomers and mixturesthereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) can exist in the salt form. Such additionsalts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids which are useful, for example, forthe purification or isolation of the compounds of formula (I) also formpart of the invention.

The compounds of formula (I) can also exist in the form of hydrates orsolvates, namely in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates alsoform part of the invention.

According to the present invention, it is possible to distinguish thecompounds of formula (I) in which:

-   -   R₁ represents hydrogen or a (C₁-C₄)alkyl;    -   R₂ represents:        -   a (C₃-C₇)alkyl group;        -   a nonaromatic C₃-C₁₀ carboxyl radical which is unsubstituted            or substituted once or several times with a (C₁-C₄)alkyl;        -   a phenyl which is substituted with a halogen atom and/or            with a (C₁-C₄)alkyl, trifluoromethyl or (C₁-C₄)alkoxy group;        -   an NR₉R₁₀ group;        -   a CH[(C₁-C₄)alkyl]benzhydryl group in which one or both of            the phenyl groups are unsubstituted or substituted with a            halogen atom or with a (C₁-C₄)alkyl or (C₁-C₄)alkoxy group;    -   or R₁ and R₂ together with the nitrogen atom to which they are        attached constitute a piperidin-1-yl radical which is        disubstituted at the 4-position with a phenyl or benzyl group        and with a (C₁-C₄)alkyl group or a (C₁-C₃)alkanoyl;    -   R₃, R₄, R₅, R₆, R₇, R₈ represent, each independently of the        other, a hydrogen or halogen atom, a (C₁-C₆)-alkyl,        (C₁-C₆)alkoxy or trifluoromethyl group;    -   provided that at least one of the substituents R₃, R₄, R₅, R₆,        R₇, R₈ is different from hydrogen;    -   R₉ represents a hydrogen atom;    -   R₁₀ represents a (C₃-C₆)alkyl;    -   or R₉ and R₁₀ together with the nitrogen atom to which they are        attached constitute a saturated or unsaturated heterocyclic        radical of 5 to 10 atoms, possibly containing a second        heteroatom chosen from O or N, said radical being unsubstituted        or substituted once or several times with a (C₁-C₄)alkyl,        hydroxyl or (C₁-C₄)alkoxy group, methoxy(C₁-C₂)alkylene, or        substituted with a spirocyclobutane, a spirocyclopentane or a        spirocyclohexane; and their salts, their solvates and their        hydrates.

In the context of the present invention, the expression:

-   -   alkyl group is understood to mean a linear or branched radical        such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,        tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, the methyl        group being preferred for a (C₁-C₄)alkyl; the tert-butyl groups,        1,1-dimethylpropyl and 2-methylbutyl-2 being preferred for a        (C₃-C₇)alkyl;    -   (C₁-C₄)alkoxy group is understood to mean a linear or branched        radical containing 1 to 4 carbon atoms, the methoxy group being        preferred;    -   halogen atom is understood to mean a fluorine, chlorine, bromine        or iodine atom, the fluorine, chlorine or bromine atoms being        preferred.    -   The C₃-C₁₀ carbocyclic or aromatic radicals comprise fused or        bridged mono- or polycyclic radicals. The monocyclic radicals        include cycloalkyls, for example cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclohexyl and        cyclopentyl being preferred. The fused, bridged or spiro di- or        tricyclic radicals include for example the        bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2.        ]octanyl, bicyclo[3.2.1]octanyl, bicyclo-[3.2.1]octanyl, and        adamantyl, bicyclo[3.1.1]heptanyl and bicyclo[3.2.1] octanyl        being preferred.

The expression saturated or unsaturated heterocyclic radical of 5 to 10atoms, containing or otherwise a second heteroatom such as O or N isunderstood to mean radicals such as morpholin-4-yl, piperidin-1-yl,piperazin-1-yl, pyrrolidin-1-yl, 3,6-dihydropyridin-1-yl, andoctahydrocyclopenta[c]-pyrrol-2-yl, the piperidin-1-yl andmorpholin-4-yl radicals being preferred.

According to the present invention, the compounds of formula (I) arepreferred in which:

-   -   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group,        preferably a hydrogen atom;    -   R₂ represents a (C₃-C₇)alkyl group or an NR₉R₁₀ group in which        R₉ and R₁₀ together with the nitrogen atom to which they are        attached constitute a piperidin-1-yl radical which is        unsubstituted or disubstituted with a 4,4-dimethyl group or        substituted at the 4-position with a spirocyclopentane group;    -   and/or one or two of the substituents R₃, R₄, R₅ represent(s) a        halogen atom or a methyl or methoxy group; preferably R₃ is at        the 4-position and represents a chlorine or bromine atom or a        methoxy group, R₄, R₅ representing a hydrogen atom;    -   and/or one or two of the substituents R₆, R₇, R₈ represent(s) a        halogen atom or a methyl group; preferably R₆ and R₇ are at the        2,4-position and represent two chlorine atoms, R₈ representing a        hydrogen atom;        and their salts, their solvates and their hydrates.

According to the present invention,

-   5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-tert-butyl-1H-pyrazole-3-carboxamide,-   5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-(1,1-dimethylpropyl)-1H-pyrazole-3-carboxamide,-   5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide,-   5-(4-methoxyphenyl)-4-cyano-1-1(2,4-dichlorophenyl)-N-tert-butyl-1H-pyrazole-3-carboxamide    and-   5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-hexahydrocyclopenta[c]pyrrol-2(1H)-yl-1H-pyrazole-3-carboxamide,    are most particularly preferred.

The subject of the present invention is also a method for preparing thecompounds according to the invention.

This method is characterized in that a functional derivative of4-cyano-1,5-diphenylpyrazole-3-carboxylic acid of formula:

in which R₃, R₄, R₅, R₆, R₇, R₈ are as defined for (I), is treated withan amine of formula HNR₁R₂ (III) in which R₁ and R₂ are as defined for(I). Optionally, the compound thus obtained is converted to one of itssalts or solvates.

As a functional derivative of the acid (II), it is possible to use thechloride of an acid, the anhydride, a mixed anhydride, a C₁-C₄ alkylester in which the alkyl is straight or branched, an activated ester,for example p-nitrophenyl ester, or the free acid opportunely activated,for example, with N,N-di-cyclohexylcarbodiimide or withbenzotriazol-N-yloxo-tris(dimethylamino)phosphonium hexafluorophosphate(BOP) or benzotriazol-1-yloxotris(pyrrolidino)-phosphoniumhexafluorophosphate (PyBOP).

Thus, in the method according to the invention, it is possible to reactthe chloride of a pyrazole-3-carboxylic acid, obtained by reactingthionyl chloride with the acid of formula (II), with an amine HNR₁R₂, inan inert solvent, such as a chlorinated solvent (dichloromethane,dichloroethane, chloroform for example), an ether (tetrahydrofuran,dioxane for example), or an amide (N,N-dimethylformamide for example)under an inert atmosphere, at a temperature of between 0° C. and roomtemperature, in the presence of a tertiary amine such as triethylamine,N-methyl-morpholine or pyridine.

An alternative method consists of preparing the mixed anhydride of theacid of formula (II) by reacting ethyl chloroformate with the acid offormula (II), in the presence of a base such as triethylamine, and inreacting it with an amine HNR₁R₂, in a solvent such as dichloromethane,under an inert atmosphere, at room temperature, in the presence of abase such as triethylamine.

The compounds of formula (II) may be prepared by various methods knownin the literature, for example as described in J. Heterocyclic Chem.,1977, 14 (3), 375-381.

In step a₁) an aniline of formula (IV) is converted to a diazonium salt(V) by the action of a nitrite in an acidic medium, as described inRazdan et al., Med. Chem. Res., 1995, 5, 54. The diazonium salt (V) isthen reacted with ethyl 2-chloro-3-oxo-butanoate (VI) to give thehydrazone derivative (VII).

The hydrazone derivative (VII) is fused with the nitrite of formula(VIII) in the presence of a strong base such as sodium ethoxide inethanol in order to obtain the pyrazole derivative (IX). The latter isfinally converted to an acid (II) by saponification using gentleconditions, for example LiOH in a THF/water mixture.

The acids of formula (II) and their esters of formula (IX) are generallynovel. Some of these compounds are described in J. Heterocyclic Chem.,1977, 14 (3), 375-381; the ethyl ester of1-(4-bromophenyl)-4-cyano-5(4-methoxyphenyl)1H-pyrazole-3-carboxylicacid is cited in the Interchim. Intermediates catalog.

Thus, the subject of the present invention is also the compounds offormula:

in which R is a hydrogen atom or a (C₁-C₄)alkyl group and R₃, R₄, R₅,R₆, R₇, R₈ are as defined for (I) provided that at least one of thesubstituents R₃, R₄, R₅ and at least one of the substituents R₆, R₇, R₈is different from hydrogen and provided that when R₃ represents amethoxy group and R₆ represents a bromine atom, the substituents R₄, R₅,R₇, R₈ are different from hydrogen.

According to the present invention, it is possible to distinguish thecompounds of formula (IIa) in which:

-   -   R₃ is at the 4-position and represents a chlorine or bromine        atom or a methyl, ethyl, trifluoromethyl or methoxy group;    -   R₆ is at the 2-position and represents a chlorine atom;    -   R₇ is at the 4-position and represents a hydrogen atom or a        chlorine atom;    -   R₄, R₅ and R₈ represent a hydrogen atom.

More particularly, the compounds of formula (IIbis) are preferred inwhich:

-   -   R₃ is at the 4-position and represents a chlorine or bromine        atom;    -   R₆ and R₇ are at the 2,4-position and represent two chlorine        atoms;    -   R₄, R₅ and R₈ represent a hydrogen atom.

The amines HNR₁R₂ are known or prepared by known methods such as thosedescribed in Chem. Ber., 1986, 119, 1413-1423.

The following examples describe the preparation of some compounds inaccordance with the invention. These examples are not limiting andmerely illustrate the present invention. The exemplified compoundnumbers refer to those given in the table below, which illustrates thechemical structures and the physical properties of a few compoundsaccording to the invention.

In the present description, the following abbreviations are used:

AcOEt: ethyl acetate; BOP:benzotriazolyloxytris-dimethylaminophosphonium hexafluorophosphate; DCM:Dichloromethane; DMF: dimethylformamide; EtOH: ethanol; m.p. meltingpoint; iPr₂O: isopropyl ether; RT: room temperature; THF:tetrahydrofuran.

The compounds according to the invention are analyzed by LC/UV/MS(liquid chromatography/UV detection/mass spectrometry) coupling. Themolecular peak (MH⁺) and the retention time (t) in minutes are measured.

There is used an Xterra Waters® MS C18 column, marketed by Waters, of2.1×30 mm, 3.5 μm, at room temperature, flow rate 1 ml/minute.

The eluent is made up as follows:

-   -   solvent A: 0.025% of trifluoroacetic acid (TFA) in water    -   solvent B: 0.025% of TFA in acetonitrile.

Gradient: The percentage of solvent B varies from 0 to 100% over 2minutes with a plateau at 100% of B for 1 minute.

The UV detection is carried out between 210 nm and 400 nm and the massdetection in chemical ionization mode at atmospheric pressure.

The NMR spectra were recorded at 200 MHz in DMSO-d₆.

For the interpretation of the nuclear magnetic resonance (NMR) spectra,the following abbreviations are used: s: singlet; d: doublet; m:unresolved complex; bs: broad singlet; dd: doublet of doublet; mt:multiplet.

Preparation 1

5-(4-Chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid

A) Ethyl chloro[(2,4-dichlorophenyl)hydrazino]acetate

7.3 g of dichloroaniline in 75 ml of a 24% HCl solution and 200 ml ofwater are mixed, with stirring, and the stirring is maintained for 2hours. The mixture is cooled in an ice bath and a solution containing3.1 g of NaNO₂ in 21 ml of water is added dropwise over 30 minutes. Themixture obtained is added to a solution containing 3.51 g of sodiumacetate and 6.21 ml of ethyl 2-chloro-3-oxobutanoate in 450 ml of EtOH,cooled in an ice bath. The temperature is allowed to rise slowly whilethe stirring is maintained. The precipitate formed is filtered, washedwith water and then dried under vacuum. 11.43 g of the expected compoundare obtained.

NMR: 1.40 ppm: t: 3H; 4.40 ppm: d: 2H; 7.40-7.80 ppm: m: 3H; 9.25 ppm:s: 1H.

B) Ethyl5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate

A mixture containing 3.27 g of the compound from the preceding step,1.99 g of 3-(4-chlorophenyl)-3-oxopropanenitrile in 120 ml of EtOH andsodium ethoxide prepared by mixing 0.28 g of sodium in 25 ml of EtOH,are heated under reflux for 18 hours. After returning to RT, the mixtureis evaporated to dryness and taken up in 150 ml of AcOEt, theprecipitate formed is filtered and the organic phase is washed withwater and then with a saturated NaCl solution. The oil obtained ischromatographed on silica, eluting with an AcOEt/toluene (2/98 to 3/97;v/v) mixture. The solid obtained is recrystallized twice from aCH₂Cl₂/iPr₂O mixture to give 1.12 g of the expected compound in the formof white crystals, m.p.=112° C.

C)5-(4-Chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid

0.436 g of the ester obtained in the preceding step in 25 ml of THF and50 mg of LiOH in 5 ml of water are mixed and the mixture is heated for 2hours at 65° C. The medium is concentrated by half, the reaction mediumis poured into 50 ml of ice-cold water and 5 ml of 5% HCl. The organicmixture is extracted with CH₂Cl₂ and then washed with NaCl. 0.41 g ofthe expected compound is obtained in solid form. m.p.=132-137° C.

NMR: 7.42 ppm: d: 2H; 7.61 ppm: d: 2H; 7.69 ppm: dd: 1H; 7.89 ppm: s:1H; 7.92 ppm: d: 1H; 13.8-14.6 ppm: bs: 1H.

Preparation 2

5-(4-Bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid

A) 3-(4-Bromophenyl)-3-oxopropanenitrile

A solution containing 9.4 g of KCN in 20 ml of water is prepared andthen it is poured dropwise over a mixture containing 20 g of2-bromo-1-(4-bromophenyl)ethanone dissolved in 800 ml of 90% ethanol.After stirring for 5 hours at RT, the solid formed is filtered and thenit is rinsed with ice-cold water. The solid obtained is dissolved in 400ml of water and then activated charcoal is added, the mixture is keptstirring for 20 minutes, and then filtered on Celite®. The filtrateobtained is treated with HCl at 10% and the white precipitate formed isfiltered, washed with water and then dried under vacuum. 7.63 g of theexpected compound are obtained. m.p.=164° C.

NMR: 4.75 ppm: bs: 2H; 7.80 ppm: mt: 4H

B) Ethyl5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate

A sodium ethoxide solution is prepared by mixing 0.86 g of sodium in 107ml of EtOH, 7.63 g of the compound prepared in the preceding step in 610ml of EtOH are rapidly added, followed by 9.2 g of the compound obtainedin step A of Preparation 1 and the reaction medium is kept stirringovernight at RT. The insoluble material is filtered and then thefiltrate is concentrated under vacuum. The product obtained isconcentrated on silica, eluting with a toluene/AcOEt (96/4; v/v)mixture. 5 g of the expected compound are obtained.

NMR: 1.25 ppm: t: 3H; 4.30 ppm: q: 2H; 7.20 ppm: d: 2H; 7.50-7.70 ppm:m: 3H; 7.70-8.00 ppm: m: 2H.

C)5-(4-Bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylicacid

2.8 g of the ester obtained in the preceding step are placed in 90 ml ofTHF and 0.4 g of LiOH in 8 ml of water are added and then the mixture isheated at 65° C. for 3 hours. The reaction medium is poured over amixture of 240 ml of ice-cold water and 16 ml of HCl at 10%. The organicphase is extracted with CH₂Cl₂ and then washed with a saturated NaClsolution. 2.3 g of the expected compound are obtained.

NMR: 7.30 ppm: d: 2H; 7.60-7.80 ppm: m: 3H; 7.80-8.00 ppm: m: 2H; 14.15ppm: bs: 1H.

By carrying out the procedure according to the procedures set forth inthe above preparations, the compounds in the following table areobtained:

TABLE 1 (II)

Preparation R₃ R₆, R₇ Melting point 3 —OMe —Cl, —Cl m.p. = 230° C. 4 —Me—Cl, —Cl m.p. = 223° C. 5 —CF₃ —Cl, —Cl m.p. = 238° C. 6 —Et —Cl, H m.p.= 254° C.

EXAMPLE 1 Compound 1

5-(4-Chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide

0.39 g of the acid from Preparation 1 is added dropwise to a solutioncontaining 0.20 ml of 1-aminopiperidine and 0.50 ml of triethylamine in15 ml of CH₂Cl₂, and then 0.80 g of BOP is added dropwise and themixture is kept stirring at RT for 20 hours. The reaction medium ishydrolyzed with water and then the organic phase is washed with a 2% HClsolution, with a 5% Na₂CO₃ solution and then with a saturated NaClsolution. After drying, the product obtained is chromatographed onsilica, eluting with an MeOH/CH₂Cl₂ (0.5/99.5; v/v) mixture to give afoam. The expected compound crystallizes from a CH₂Cl₂/iPr₂O mixture,0.28 g is obtained, m.p.=227-229° C.

EXAMPLE 2 Compound 12

5-(4-Bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-tert-butyl-1H-pyrazole-3-carboxamide

0.437 g of the acid from Preparation 2, 0.19 ml of tert-butylamine, 0.5ml of NEt₃ and then 0.79 g of BOP are mixed in 20 ml of CH₂Cl₂ and themixture is kept stirring at RT for 48 hours. The reaction medium ishydrolyzed with water and then the organic phase is washed with a 2% HClsolution, a 5% Na₂CO₃ solution and then a saturated NaCl solution. Afterdrying, the product obtained is chromatographed on silica, eluting witha toluene/AcOEt (95/5; v/v) mixture to give a product which crystallizesfrom isopropyl ether. 370 mg are obtained, m.p.=184° C.

NMR: 1.35 ppm; s: 9H; 7.30 ppm: d: 2H; 7.60-8.00 ppm; m: 6H.

The table which follows illustrates the chemical structure and thephysical properties of a few examples of compounds according to theinvention.

In this table, Me, Et and tBu represent the methyl, ethyl and tert-butylgroups, respectively.

TABLE 2 (I)

Compounds R₃ R₆, R₇ —NR₁R₂ characterization 1 —Cl —Cl, —Cl

m.p. = 227° C. 2 —Br —Cl, —Cl

m.p. = 228° C. 3 —Cl —Cl, —Cl —NH-tBu m.p. = 197° C. 4 —Cl —Cl, —Cl

m.p. = 159° C. 5 —Cl —Cl, —Cl

m.p. = 243° C. 6 —Cl —Cl, —Cl

m.p. = 233° C. 7 —Cl —Cl, —Cl

m.p. = 200° C.+polar 8 —Cl —Cl, —Cl

m.p. = 241° C.−polar 9 —Br —Cl, —Cl

m.p. = 231° C. 10 —Br —Cl, —Cl

m.p. = 252° C. 11 —Br —Cl, —Cl

m.p. = 160° C. 12 —Br —Cl, —Cl —NH-tBu m.p. = 184° C. 13 —Br —Cl, —Cl

m.p. = 212° C.+polar 14 —Br —Cl, —Cl

m.p. = 250° C.−polar 15 —Cl —Cl, —Cl

MH⁺ = 577t = 2.59 16 —Cl —Cl, —Cl

MH⁺ = 527t = 2.78 17 —Cl —Cl, —Cl

MH⁺ = 497t = 2.52 18 —Cl —Cl, —Cl

MH⁺ = 485t = 2.55 19 —Cl —Cl, —Cl

MH⁺ = 619t = 2.71 20 —Cl —Cl, —Cl

MH⁺ = 499t = 2.80 21 —Br —Cl, —Cl

m.p. = 209° C. 22 —OMe —Cl, H

m.p. = 260° C. 23 —OMe —Cl, —Cl —NH-tBu m.p. = 229° C. 24 —Et —Cl, H

m.p. = 227° C. 25 —Et —Cl, —Cl —NH-tBu m.p. = 225° C. 26 —Et —Cl, H

m.p. = 192° C. 27 —Br —Cl, —Cl

m.p. = 222° C. 28 —CF₃ —Cl, —Cl —NH-tBu m.p. = 192° C. 29 —CF₃ —Cl, —Cl

m.p. = 223° C. 30 —CF₃ —Cl, —Cl

m.p. = 177° C. 31 —OMe —Cl, —Cl —NH-tBu m.p. = 157° C. 32 —OMe —Cl, —Cl

m.p. = 180° C. 33 —OMe —Cl, —Cl

m.p. = 143° C. 34 —Me —Cl, —Cl —NH-tBu m.p. = 171° C. 35 —Cl —Cl, —Cl

m.p. = 239° C. 36 —Me —Cl, —Cl

m.p. = 157° C. 37 —Me —Cl, —Cl

m.p. = 206° C. 38 —OMe —Cl, —Cl

m.p. = 197° C. 39 —OMe —Cl, —Cl

m.p. = 206° C. 40 —OMe —Cl, —Cl

m.p. = 266° C. 41 —OMe —Cl, —Cl

m.p. = 196° C. 42 —OMe —Cl, —Cl

m.p. = 164° C.

The compounds according to the invention have been the subject ofpharmacological trials which make it possible to determine theirantagonist effect of CB₁, cannabinoid receptors.

The compounds of formula (I) possess a very good affinity in vitro(IC₅₀≦10⁻⁷M) for the CB₁ cannabinoid receptors, under the experimentalconditions described by M. Rinaldi-Carmona et al. (FEBS 1994, 350,240-244).

The antagonist nature of the compounds of formula (I) has beendemonstrated by the results obtained in adenylate cyclase inhibitionmodels as in M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996,278, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272,22330-22339.

The compounds according to the invention were tested in vivo (binding exvivo) in mice after intravenous and/or oral administration, according tothe experimental conditions described by Rinaldi-Carmona et al. (J.Pharmacol. Exp., 1998, 284, 644-650). By the intravenous route, theeffective dose (ED₅₀) of these compounds for the CB₁ receptors is lessthan or equal to 10 mg/kg. By the oral route, compounds 2, 3, 4, 11 and12 have an ED₅₀ of between 1 and 20 mg/kg for the CB₁ receptors.

The toxicity of the compounds of formula (I) is compatible with theiruse as a medicament.

According to another of these aspects, the present invention relates tothe use of a compound of formula (I), or of one of its pharmaceuticallyacceptable salts, solvates or hydrates, for the preparation ofmedicaments intended for treating or preventing diseases involving theCB₁ cannabinoid receptors.

For example and without limitation, the compounds of formula (I) areuseful as psychotropic medicaments, in particular for the treatment ofpsychiatric disorders including anxiety, depression, mood disorders,insomnia, delirium disorders, obsessive disorders, psychoses in general,schizophrenia, attention deficit hyperactivity disorder (ADHD), inparticular in hyperkinetic children (MBD), and for the treatment ofdisorders linked to the use of psychotropic substances, in particular inthe case of a substance abuse and/or of dependence on a substance,including alcohol dependence and nicotine dependence.

The compounds of formula (I) according to the invention may be used asmedicaments for the treatment of migraine, stress, diseases ofpsychosomatic origin, panic attacks, epileptic attacks, motiondisorders, in particular dyskinesia or Parkinson's disease, tremors anddystonia.

The compounds of formula (I) according to the invention can also be usedas medicaments in the treatment of memory disorders, cognitivedisorders, in particular in the treatment of senile dementia,Alzheimer's disease, and in the treatment of attention or vigilancedisorders. Furthermore, the compounds of formula (I) may also be usefulas neuroprotectants, in the treatment of ischemia, cranial traumas andthe treatment of neurodegenerative diseases: including chorea,Huntington's chorea, Tourette's syndrome.

The compounds of formula (I) according to the invention can be used asmedicaments in the treatment of pain: neuropathic pain, acute peripheralpain, chronic pain of inflammatory origin.

The compounds of formula (I) according to the invention may be used asmedicaments in the treatment of appetite disorders, craving disorders(for sugars, carbohydrates, drugs, alcohol or any appetizing substance)and/or alimentary canal disorders, in particular as anorexics or for thetreatment of obesity or of bulimia and for the treatment of type IIdiabetes or non-insulin-dependent diabetes and for the treatment ofdyslipidemia and of metabolic syndrome. Furthermore, the compounds offormula (I) according to the invention may be used as medicaments in thetreatment of gastrointestinal disorders, diarrheal disorders, ulcers,emesis, bladder and urinary disorders, disorders of endocrine origin,cardiovascular disorders, hypotension, hemorrhagic shock, septic shock,chronic cirrhosis of the liver, asthma, chronic bronchitis and chronicobstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertilitydisorders, inflammatory phenomena, immune system diseases, in particularautoimmune and neuroinflammatory diseases such as rheumatoid arthritis,reactive arthritis, diseases causing demyelinization, multiplesclerosis, infectious and viral diseases such as encephalitis, strokeand as medicaments for anticancer chemotherapy and for the treatment ofGuillain-Barré syndrome.

According to the present invention, the compounds of formula (I) areparticularly useful for the treatment of psychotic disorders, inparticular schizophrenia, attention deficit hyperactivity disorders(ADHD), in particular in hyperkinetic children (MBD); for the treatmentof appetite disorders and obesity, for the treatment of memory andcognitive disorders; for the treatment of alcohol dependence, nicotinedependence, that is to say for withdrawal from alcohol and for smokingcessation; and for the treatment of dyslipidemia and of metabolicsyndrome.

According to one of its aspects, the present invention relates to theuse of a compound of formula (I), of its pharmaceutically acceptablesalts and of their solvates or hydrates, for the treatment of thedisorders and diseases indicated above.

The compounds of formula (I) according to the invention may be used incombination with one or more other active ingredients useful for theprevention and/or treatment of the diseases indicated above: by way ofexample of active ingredients which may be combined with a compound offormula (I), there may be mentioned antipsychotics, anxiolytics, memoryenhancers, anti-Parkinson agents, antiepileptics, anorexics or otherantiobesity agents, nicotine agonists, monoamine oxidase inhibitors,analgesics, antiinflammatory agents, antihypertensives such as:angiotensin II AT₁ receptor antagonists, converting enzyme inhibitors,calcium antagonists, beta-blockers, antidiabetics, antihyperlipidemics,anticholesterolemics, PPAR (peroxisome proliferator activated receptor)agonists.

The compound according to the invention is generally administered indosage unit form.

Said dosage units are preferably formulated in pharmaceuticalcompositions in which the active ingredient is mixed with apharmaceutical excipient.

Thus according to another of its aspects, the present invention relatesto pharmaceutical compositions containing, as active ingredient, acompound of formula (I), one of its pharmaceutically acceptable salts orone of their solvates.

The compound of formula (I) above and its pharmaceutically acceptablesalts or solvates may be used in daily doses of 0.01 to 100 mg per kg ofbody weight of the mammal to be treated, preferably in daily doses of0.02 to 50 mg/kg. In human beings, the dose can vary preferably from0.05 to 4000 mg per day, more particularly from 0.1 to 1000 mg per dayaccording to the age of the subject to be treated or the type oftreatment, namely prophylactic or curative. Although these dosages areexamples of average situations, there may be particular cases whenhigher or lower dosages are appropriate, such dosages also belong to theinvention. According to customary practice, the dosage appropriate foreach patient is determined by the doctor according to the mode ofadministration, the age, the weight and the response of said patient.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhaled, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active ingredient maybe administered in unit form for administration, mixed with conventionalpharmaceutical carriers, to animals and to humans. The appropriate unitforms for administration comprise the forms by the oral route such astablets, gelatin capsules, powders, granules and oral solutions orsuspensions, the forms for sublingual or buccal administration,aerosols, the forms for topical administration, implants, the forms forsubcutaneous, intramuscular, intravenous, intranasal or intraocularadministration and the forms for rectal administration.

In the pharmaceutical compositions of the present invention, the activeingredient is generally formulated in dosage units containing from 0.05to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200mg of said active ingredient per dosage unit for daily administrations.

By way of example, a unit form for administration of a compoundaccording to the invention in tablet form may comprise the followingcompounds:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium  6.0 mg Maize starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

By the oral route, the dose of active ingredient administered per daymay be up to 0.01 to 100 mg/kg, in single or divided doses, preferably0.02 to 50 mg/kg.

There may be specific cases where higher or lower doses are appropriate;such doses do not depart from the scope of the invention. According tothe usual practice, the appropriate dose for each patient is determinedby the doctor according to the mode of administration, the weight andthe response of said patient.

The present invention, according to another of its aspects, also relatesto a method for treating the pathologies indicated above, whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts or hydrates or solvates.

1. A compound of formula (I):

in which: R₁ represents hydrogen or a (C₁-C₄)alkyl; R₂ represents: anNR₉R₁₀ group; R₃, R₄, R₅, R₆, R₇, R₈ represent, each independently ofthe other, a hydrogen, halogen, a (C₁-C₆)alkyl, (C₁-C₆)alkoxy ortrifluoromethyl; provided that at least one of the substituents R₃, R₄,R₅, R₆, R₇, R₈ is different from hydrogen; R₉ represents a hydrogenatom; R₁₀ represents a (C₃-C₆)alkyl; or R₉ and R₁₀ together with thenitrogen atom to which they are attached constitute a saturated orunsaturated heterocyclic radical of 5 to 10 atoms, optionally containinga second heteroatom chosen from O or N, said radical being unsubstitutedor substituted once or several times with a (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, methoxy(C₁-C₂)alkylene, (C₁-C₄)alkanoyl group orsubstituted with a spirocyclobutane, a spirocyclopentane or aspirocyclohexane; or a pharmaceutically acceptable salt thereof or ahydrate or a solvate thereof.
 2. The compound of formula (I), as setforth in claim 1, wherein: R₁ represents hydrogen or a (C₁-C₄)alkyl; R₂represents an NR₉R₁₀ group in which R₉ and R₁₀ together with thenitrogen atom to which they are attached constitute a piperidin-1-ylradical which is unsubstituted or disubstituted with a 4,4-dimethylgroup or substituted at the 4-position with a spirocyclopentane group;at least one of the substituents R₃, R₄ or R₅ represents a halogen atom,a methyl or methoxy; and at least one of the substituents R₆, R₇ or R₈represents a halogen atom or a methyl; or a pharmaceutically acceptablesalt thereof or a hydrate or a solvate thereof.
 3. The compound offormula (I), as set forth in claim 1, wherein: R₁ represents hydrogen;R₂ represents an NR₉R₁₀ group in which R₉ and R₁₀ together with thenitrogen atom to which they are attached constitute a piperidin-1-ylradical which is unsubstituted or disubstituted with a 4,4-dimethylgroup or substituted at the 4-position with a spirocyclopentane group;R₃ is at the 4-position and represents chlorine, bromine or methoxy; R₄and R₅ are hydrogen; R₆ and R₇ are at the 2,4-position and represent 2chlorine atoms; and R₈ is hydrogen; or a pharmaceutically acceptablesalt thereof or a hydrate or a solvate thereof.
 4. The compound, as setforth in claim 1, chosen from:5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamideand5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide;or a pharmaceutically acceptable salt thereof or a hydrate or a solvatethereof.
 5. A method for preparing a compound of formula (I) as setforth in claim 1, comprising reacting4-cyano-1,5-diphenylpyrazole-3-carboxylic acid of formula II or afunctional derivative thereof:

in which R_(3, R) ₄, R₅, R₆, R₇, R₈ are as defined in claim 1, with anamine of formula HNR₁R₂ (III) in which R₁ and R₂ are as defined inclaim
 1. 6. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt, a hydrate or asolvate thereof, in combination with at least one pharmaceuticallyacceptable excipient:

in which: R₁ represents hydrogen or a (C₁-C₄)alkyl; R₂ represents: anNR₉R₁₀ group; R₃, R₄, R₅, R₆, R₇, R₈ represent, each independently ofthe other, a hydrogen, halogen, a (C₁-C₆)alkyl, (C₁-C₆)alkoxy ortrifluoromethyl; provided that at least one of the substituents R₃, R₄,R₅, R₆, R₇, R₈ is different from hydrogen; R₉ represents a hydrogenatom; R₁₀ represents a (C₃-C₆)alkyl; or R₉ and R₁₀ together with thenitrogen atom to which they are attached constitute a saturated orunsaturated heterocyclic radical of 5 to 10 atoms, optionally containinga second heteroatom chosen from O or N, said radical being unsubstitutedor substituted once or several times with a (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, methoxy(C₁-C₂)alkylene, (C₁-C₄)alkanoyl group orsubstituted with a spirocyclobutane, a spirocyclopentane or aspirocyclohexane.
 7. The composition as set forth in claim 6 wherein: R₁represents hydrogen or a (C₁-C₄)alkyl; R₂ represents an NR₉R₁₀ group inwhich R₉ and R₁₀ together with the nitrogen atom to which they areattached constitute a piperidin-1-yl radical which is unsubstituted ordisubstituted with a 4,4-dimethyl group or substituted at the 4-positionwith a spirocyclopentane group; at least one of the substituents R₃, R₄or R₅ represents a halogen atom, a methyl or methoxy; and at least oneof the substituents R₆, R₇ or R₈ represents a halogen atom or a methyl.8. The composition as set forth in claim 6, wherein: R₁ representshydrogen; R₂ represents an NR₉R₁₀ group in which R₉ and R₁₀ togetherwith the nitrogen atom to which they are attached constitute apiperidin-1-yl radical which is unsubstituted or disubstituted with a4,4-dimethyl group or substituted at the 4-position with aspirocyclopentane group; R₃ is at the 4-position and representschlorine, bromine or methoxy; R₄ and R₅ are hydrogen; R₆ and R₇ are atthe 2,4-position and represent 2 chlorine atoms; and R₈ is hydrogen. 9.The composition as set forth in claim 6, wherein said compound is chosenfrom:5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamideand5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide;or a pharmaceutically acceptable salt thereof or a hydrate or a solvatethereof.